This proposal outlines a plan for a Phase 1b clinical trial for the injection of human spinal cord derived stem cells (HSSCs) into the cervical spinal cord of patients with ALS. This trial is a follow up to a trial already underway at Emory University, where 12 ALS patients have been injected with the same HSSCs into the lumbar spinal cord. In order to move this therapeutic approach closer to a clinical trial to determine if t is effective in ameliorating disease, we are proposing to test the safety of HSSC injection into the cervical spinal cord. Motor neurons in the cervical spinal cord innervate the respiratory diaphragm, the loss of which is typically the cause of death in ALS patients. We propose that the protection of these neurons is likely to prolong life by preserving respiratory function. This safety trial will employ progressive dose escalation to determine the maximum tolerated dose that can be used for the long term goal of performing Phase 2 and Phase 3 efficacy trials. There are two specific aims. In Aim 1 we propose to sequentially escalate the dose of delivery as defined by 1) the number of cells/injection, 2) the number of injections into the cord, and 3) either unilateral or bilateral injections. This dose escalation scheme is designed to safely and efficiently test our ability to achieve a pre-defined target therapeutic dose, which can be used in the next phase of testing therapeutic efficacy. Aim 2 of this proposal is to examine several exploratory endpoints that may be used to test the efficacy of this therapy in future Phase 2 and Phase 3 trials. These include measures of respiratory function, diaphragm function, muscle strength, and electrical characteristics of muscle (Electrical Impedance Myography). Successful completion of this Phase 1b trial will allow for testing of this highly innovative approach to the treatment of ALS. The impact will extend beyond patients with ALS since this novel trial will provide data on surgical approach and safety, as well as trial design that will be highly relevant to cellular therapeutics for spinal cord injury, multiple sclerosis, spinal muscular atrophies, as well as other neurological diseases.